Cyanohydrins of the structure ##STR1## where R.sub.1 and R.sub.2 are selected from hydrogen and substituted or unsubstituted alkyl or aryl, are important starting materials and intermediates in the preparation of a large number of biologically active compounds. See for example, 99 Ang. Chemie 491 (1987). When R.sub.1 and R.sub.2 are different, such cyanohydrins are chiral and so exist as (R)- and (S)-enantiomers, generally in equal proportions, known as racemic mixtures. When cyanohydrin derivatives that contain chiral centers are used to prepare biologically active substances, it is often highly desirable that they be in an enantiomerically-enriched or pure form, as opposed to in a racemic mixture, so as to improve biological specificity and reduce side effects.
Cyanohydrins are generally prepared by hydrocyanation, which involves adding hydrogen cyanide to aldehydes or ketones. Several methods used to synthesize enantiomerically-enriched cyanohydrins use chiral hydrocyanation catalysts to catalyze enantioselective addition of hydrogen cyanide to aldehydes and ketones according to the general reaction ##STR2## where, for example, the products contain a greater percentage ("enantiomeric excess") of one enantiomer relative to the other enantiomer. Such syntheses are known as asymmetric cyanohydrin syntheses. Known enantioselective hydrocyanation catalysts useful in such asymmetric cyanohydrin syntheses include (R)- and (S)-oxynitrilases (see 46 Tet. 979 (1990) for (R)-oxynitrilases and 31 Tet. Lett. 1249 (1990) for (S)-oxynitrilases); cyclic peptides (see for example U.S. Pat. No. 4,569,793 for use of cyclo-(R)-phenylalanyl-(R)-histidine and cyclo-(S)-phenylalanyl-(S)-histidine dipeptides); cyclodextrins (see 39 Aust. J. Chem. 1135 (1986) for use of crystalline .beta.-cyclodextrin complexes); tartaric acid complexes (see European Patent Application No. 0 271 868 for use of titanium complexes); and rhenium .pi.-aldehyde complexes (see for example, 30 Tet. Lett. 3931 (1989)). However, these asymmetric cyanohydrin syntheses frequently produce products of inadequate enantiomeric excess because of the competing non-enantioselective base-catalyzed hydrocyanation reaction. Consequently, there is a need for alternative methods to produce chiral cyanohydrins in enantiomerically enriched or pure form.
An alternative to using an enantioselective hydrocyanation catalyst to prepare chiral cyanohydrins is enantioselective dehydrocyanation, that is, the use of an enantioselective catalyst to effect the enrichment of a mixture of chiral cyanohydrins by preferentially converting one enantiomer in the mixture into hydrogen cyanide and the corresponding aldehyde or ketone. Such a reaction may be depicted by the equation below. ##STR3## In principle, such a reaction can transform a mixture of cyanohydrin enantiomers into a mixture of cyanohydrins enriched in one enantiomer, the corresponding aldehyde or ketone, and hydrogen cyanide.
There are a few reports that describe enantioselective catalysts that preferentially convert one enantiomer in a mixture of cyanohydrins into hydrogen cyanide and the corresponding aldehyde or ketone. Gerstner et al., in 353 Z. Physiol. Chem. 271 (1972), reported that the enzyme D-oxynitrilase (D-alphaoxynitrile lyase, EC 4.1.2.10) catalyzes the reversible addition of hydrogen cyanide to a variety of aldehydes to form D-cyanohydrins. Mao et al., in 6 Phytochemistry 473 (1967), reported that the oxynitrilase enzyme from sorghum appears to be specific for the dehydrocyanation of p-hydroxybenzaldehyde cyanohydrin.
U.S. Pat. No. 3,649,457 discloses the enantioselective dehydrocyanation of D,L-mandelonitrile (benzaldehyde cyanohydrin) to enrich the same in L-mandelonitrile with an (R)-oxynitrilase catalyst that is attached to a soluble polymer to maintain it in the reaction solution, yet cause it to be rejected by an ultrafiltration membrane that allows all reactants and reaction products to pass. There is no teaching of simultaneous trapping or removal of either the aldehyde or HCN, nor of the advantages which flow therefrom.
Dehydrocyanation reactions are characterized by unfavorable dehydrocyanation equilibria; the equilibrium of a typical dehydrocyanation reaction strongly favors formation of the cyanohydrin. For example, given the dehydrocyanation equilibrium constant for benzaldehyde cyanohydrin of 5 mM, a 1M solution of benzaldehyde cyanohydrin exposed to a dehydrocyanation catalyst will undergo only about 7% conversion to benzaldehyde and hydrogen cyanide when allowed to reach equilibrium. Enantioselective dehydrocyanation represents a kinetic resolution, and such a resolution is optimally carried out under conditions where the equilibrium strongly favors formation of the products. Because the equilibrium of a dehydrocyanation reaction strongly favors reactants, such a reaction would not appear to lend itself for use in a kinetic resolution.